We will idenify and characterize CSC from EGFR-driven lung cancer that are mainly found in non-smokers, compare these findings with tabacco-induced K-Ras associated tumors, as well as examine the premalignant niche that supports lung CSC. Phenotypic and functional characterization will be followed by lung CSC isolation, analysis of miRNA and gene expression, epigenetic changes and responses to therapies. We will use EGFR and K-Ras driven transgenic and tabacco carcinogen-induced mouse models, human cell lines, and clinical samples from lung cancer patients. The analysis of CSC biology will support drug testing and clinical development of lung CSC directed therapies. Specific aim 1: identification and characterization of lung cancer stem cells derived from human and murine lung cancer. a)identification of CSC in K-Ras driven lung cancer b)identification of CSC in EGFR driven lung cancer c)identification of CSC in premalignant lung lesions and during tobacco induced tumorigenesis d)molecular characterization of lung CSC Specific aim 2: modulation of lung CSC survival and self-renewal. a)genetic approaches b)pharmacologic approaches c)toxicologic approaches